Pancreatin is a substance which is derived from mammalian pancreas glands and comprises different digestive enzymes such as lipases, amylases and proteases. Pancreatin has been used to treat pancreatic exocrine insufficiency which is often associated with cystic fibrosis, chronic pancreatitis, post-pancreatectomy, post-gastrointestinal bypass surgery (e.g. Billroth II gastroenterostomy) and ductal obstruction from neoplasm (e.g. of the pancreas or common bile duct). For the application of pancreatin in pharmacological products it is preferred to substantially maintain the intrinsic high level of activity of the different digestive enzymes. However, these enzymes can be subject to degradation, e.g., upon storage, and are particularly sensitive to elevated temperatures. Thus, pancreatin requires carefully controlled conditions during the overall handling, manufacturing and storage process.
Due to the animal origin of pancreatin, this may further comprise other components which are unwanted such as one or more biological contaminants. During more than 100 years of commercialization of pharmaceutical products containing pancreatin, no case has been reported where patients have been affected by pancreatin contaminated by any virus. However, companies producing pharmaceutical products derived from biological tissues and/or body fluids experience increasing pressure from the regulatory bodies to increase the level of safety of their products by reducing all kinds of contaminants to the lowest level possible, independent of whether any concerned contaminant is considered a human pathogen or not. For the application of pancreatin in pharmacological products, it is therefore desirable to minimize the concentration of biological contaminants therein down to generally accepted detection limits.
Hence, for the manufacturing, handling and storage process of pancreatin, the skilled person is faced with the challenge of tailoring such processes in a way that a high level of activity of the different digestive enzymes is maintained while at the same time the concentration of one or more biological contaminants therein is minimized.
The current manufacturing processes of pancreatin would not seem to allow efficient inactivation of biological contaminants, in particular of specific viruses.
Different approaches are known to reduce the concentrations of viruses and bacteria within enzymatic compositions. Such methods include heat treatment, filtration, the addition of chemical inactivants or sensitizers, treatment with irradiation and extended heating. These methods are described below.
Heat treatment implies that the product e.g. be heated to 60° C. for 70 hours which can be damaging to sensitive products. In some instances, conventional heat inactivation can actually destroy a substantial amount of the enzymatic activity of a product.
Filtration involves filtering the product in order to physically remove contaminants. Unfortunately, this method may also remove products having a high molecular weight. Further, in certain cases, small viruses and similarly sized contaminants and pathogens may not be removed by the filter.
The procedure of chemical sensitization involves the addition of noxious agents which bind to the DNA/RNA of the virus and which are activated by either UV or other radiation. The radiation produces reactive intermediates and/or free radicals which bind to the DNA/RNA of the virus, break the chemical bonds in the backbone of the DNA/RNA, and/or crosslink or complex it in such a way that the virus can no longer replicate. This procedure requires unbound sensitizer to be washed from products since the sensitizers are toxic, if not mutagenic or carcinogenic, and cannot be administered to a patient.
U.S. Pat. No. 3,956,483 (Lewis) discloses a method of preparing pancreatin having suitable amylolytic, proteolytic and lipolytic activities and of eliminating harmful bacteria therefrom while maintaining said activities. Said method comprises heating the pancreatin to a sufficiently high temperature between 120° F. and 180° F. (approx. 49-82° C.). Lewis, however, fails to provide a process which would be suitable to minimize the concentration of viruses down to presently accepted detection limits.
U.S. Pat. No. 6,749,851 (Mann) suggests the treatment of compositions comprising digestive enzymes by stabilizing the compositions in a first step by either (a) reducing the temperature of, (b) reducing the solvents of, or (c) adding a stabilizer to the composition, followed by irradiation of the composition in a second step.
Braeuniger et al. (Braeuniger et al., Int. J. Hyg. Environ. Health 203, 71-75, 2000) suggest the use of heat for the inactivation of the bovine parvovirus. It has been demonstrated that the bovine parvovirus which can be deactivated is dependent upon exposure and residual moisture. In general, higher moisture contents allow shorter heat exposure durations providing the same inactivation as a lower moisture content in combination with a longer exposure duration. However, Braeuniger et al. do not disclose anything about the effect that heat has on enzymes such as lipases, amylases and proteases forming part of animal pancreatin. Thus, there is a need for a process which provides pancreatin having enzymes with a high level of activity while sufficiently reducing the concentration of biological contaminants.
It has now been found that select conditions can be employed in the manufacture of pancreatin in which the concentration of one or more biological contaminants therein has been reduced and in which the enzyme activity is maintained at an acceptable level. In particular, it has been found that a process as disclosed and claimed herein is useful to decrease the concentration of viral contaminants in pancreatin. Furthermore, the process described herein has been found to effectively meet various regulatory requirements regarding the removal of viruses from biological products (e.g. “Note For Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses”, issued from the Committee For Proprietary Medicinal Products (herein after referred to as “CPMP/BWP/268/95”)) while at the same time maintaining enzyme activities (e.g. lipase, protease and amylase) at an acceptable level.
Another advantage of the process described herein, and the resulting pancreatin, as well as the pharmaceutical compositions comprising the pancreatin obtained by the process described herein, is its applicability for laboratory scale, pilot scale and production scale.